The role of chromatin in T cell gene transcription

Abstract

Specific chromatin characteristics, especially the modification status of the core histone proteins, are associated with active and inactive genes. There is also growing evidence that genes that respond to environmental or developmental signals may possess distinct chromatin marks. Using two approaches, mining of ChIP-seq data and ChIP-qPCR for individual genes, this thesis sought to define the chromatin signature of inducible genes in T cells. Inducible genes with low basal expression, especially rapidly induced primary response genes (genes that do not need new protein synthesis), are more likely to display the histone modifications of active genes than their non-responsive counterparts. In addition, the majority of inducible, low basal expression genes with an active chromatin signature also have RNA polymerase II (Pol II) at their promoters suggesting a close link between Pol II recruitment and the presence of active chromatin marks. In tum, the majority of these genes show evidence of ongoing elongation as measured by the presence of H3K36me3, a mark of elongation, in the gene body. In contrast, genes with slower kinetics of expression (secondary response genes that need new protein synthesis) have less active chromatin marks and Pol II at the promoter. Following T cell activation, there was little evidence for a major shift in the active chromatin signature around inducible gene promoters but many genes recruit more Pol II and show increased evidence of elongation. These results suggest that the majority of inducible genes are primed for activation by having an active chromatin signature and a basal level of Pol II activity. Ultimately, these studies contribute to the growing knowledge of the epigenetic landscape and highlight the importance of chromatin regulation ofinducible gene expression in the immune response of a complex organism.